Nebivolol (hereafter NBV), is a mixture of equal amounts of [2S [2R*[R[R*]]]]α,α′-[imino-bis(methylene)]bis[6-fluoro-chroman-2-methanol] (hereafter d-NBV) of formula (IA)
and its [2R [2S*[S[S*]]]] enantiomer (hereafter l-NBV) of formula (IB)

Nebivolol is characterised by its β-adrenergic blocking properties and is useful in treating essential hypertension. It has basic properties and may be converted into its addition salts through treatment with suitable acids. The hydrochloric acid addition salt is the marketed product.
It is known in the art that the synthesis of α,α′-[imino-bis(methylene)]bis[chroman-2-methanol] molecular structures is challenging for the skilled person because of the 4 asymmetric carbon atoms producing a mixture of 16 stereoisomers (in case of asymmetrical substitutions) or a mixture of 10 stereoisomers (in case of symmetrical substitutions). As apparent from the presence of symmetry in the structure of nebivolol, a total of 10 stereoisomers may be generated.
Literature reports several processes for the preparation of nebivolol.
Patent EP 145067 describes a process of preparing NBV which comprises synthesizing diastereoisomeric mixtures of chroman epoxide derivatives in accordance with the synthetic scheme below

The 6-fluoro chroman carboxylic acid ethyl ester, derived from the esterification of the corresponding acid, is reduced with sodium dihydro bis-(2-methoxyethoxy)-aluminate to a primary alcohol; the product is reacted with oxalyl chloride and then triethylamine at −60° C. to give the corresponding racemic aldehyde, which is then converted into an epoxide as a mixture of (R,S), (S,R), (R,R) and (S,S) stereoisomers.
Said epoxide derivatives represent the key intermediates of the process.
Patent EP 334429 mainly describes the same synthetic process reported in the previous patent and is particularly directed to the preparation of the single optical isomers (R,S,S,S) and (S,R,R,R) of NBV.
In this instance, the 6-fluoro chroman carboxylic acid is resolved into single enantiomers by treatment with (+)-dehydroabiethylamine. Said single enantiomers are separately converted into their corresponding epoxides resulting in a mixture of two diastereoisomers. The following synthetic scheme describes, for example, the conversion of the S-acid derivative.

Co-pending international patent application WO 2008/040528 in the name of the same Applicant describes an improved process for the preparation of 6-fluorochroman epoxides via alpha-haloketone which comprises the conversion of an alkyl or aryl 6-fluoro-3,4-dihydro-2H-chromen-2-carboxylate into 2-halo-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanone; reducing said alpha-haloketone derivative to give the corresponding 2-halo-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol; and cyclizing in the presence of a base to give an epoxide derivative as a mixture of four stereoisomers.
In particular, said conversion step is carried out by reacting an alkyl or aryl chroman carboxylate with a sulfoxonium ylide to give the keto sulfoxonium ylide which is transformed into an alpha-haloketone by reaction with anhydrous halogenhydric acids optionally generated in situ.
International patent application WO 2008/010022 (Cimex Pharma and University of Zurich) describes a process of making racemic nebivolol and its pure enantiomers and pharmaceutically acceptable salts thereof.
The method entails, inter alia, providing a racemic alpha-haloketone of formula
and its conversion into a 6-fluoro-chroman epoxide; in particular said step of providing a compound of formula V comprises(1) transforming a compound of formula
into an activated acid derivative;(2) reacting the activated acid derivative with Meldrum's acid in the presence of a base to give a compound of formula
(3) converting the compound of formula III into a compound of formula
wherein R is hydrogen or COOR′ and wherein R′ is C1-C6 alkyl or aryl-C1 alkyl; and(4) halogenating the compound of formula IV and optionally conducting hydrolysis and decarboxylation to give the compound of formula V.
It is apparent from the prior art that alpha-haloketones play an essential role in the preparation of 6-fluoro-chroman epoxide derivatives and, in turn, of the active pharmaceutical ingredient nebivolol.
Purpose of the Invention
Hence, it would be desirable to study alternative methods for preparing the intermediate of formula I in racemic form or in the form of its single stereoisomers with good yields and under conditions more favourable from the industrial application point of view.